Comparison of small molecules and oligonucleotides that target a toxic, non-coding RNA

Costales, Matthew G.; Rzuczek, Suzanne G.; Disney, Matthew D.

doi:10.1016/j.bmcl.2016.04.025

Cited by 16 publications

(18 citation statements)

References 23 publications

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“…Given the potential advantages of small molecule chemical probes over biological approaches (e.g. siRNAs, ASOs and CRISPR-Cas) ( 13 , 14 ) and the power of using both approaches in tandem ( 12 ), the development of RNA-targeted chemical probes has the potential to greatly benefit both chemists and biologists interested in RNA.…”

Section: Introductionmentioning

confidence: 99%

Insights into the development of chemical probes for RNA

Morgan

Forte

Hargrove

2018

Nucleic Acids Research

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Over the past decade, the RNA revolution has revealed thousands of non-coding RNAs that are essential for cellular regulation and are misregulated in disease. While the development of methods and tools to study these RNAs has been challenging, the power and promise of small molecule chemical probes is increasingly recognized. To harness existing knowledge, we compiled a list of 116 ligands with reported activity against RNA targets in biological systems (R-BIND). In this survey, we examine the RNA targets, design and discovery strategies, and chemical probe characterization techniques of these ligands. We discuss the applicability of current tools to identify and evaluate RNA-targeted chemical probes, suggest criteria to assess the quality of RNA chemical probes and targets, and propose areas where new tools are particularly needed. We anticipate that this knowledge will expedite the discovery of RNA-targeted ligands and the next phase of the RNA revolution.

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Section: Introductionmentioning

confidence: 99%

Insights into the development of chemical probes for RNA

Morgan

Forte

Hargrove

2018

Nucleic Acids Research

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“…We demonstrated that RNA repeats can template the synthesis of their own inhibitors using a click reaction in cellulis, including in DM1 patient-derived cells [22,31]. Notably, the clickable compounds developed for DM1 and DM2 are the most potent RNA-targeting small molecules identified to date with pM and nM EC50's for rescuing disease-associated defects in cells, respectively, and are 50,000-fold more potent than the corresponding repeat-targeting oligonucleotides [31,32].…”

Section: Resultsmentioning

confidence: 99%

A Toxic RNA Catalyzes the Cellular Synthesis of Its Own Inhibitor, Shunting It to Endogenous Decay Pathways

Benhamou

Angelbello

Wang

et al. 2019

Preprint

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2 HIGHLIGHTS• Intron retention in RNA repeat expansions can be due to repeats binding to proteins • Small molecules that bind RNA repeats and inhibit protein binding can trigger decay • A toxic RNA repeat can catalyze the synthesis of its own inhibitor on-site• On-site drug synthesis most potently affects disease biology eTOC BLURBThe most common way to target RNA is to use antisense oligonucleotides to target unstructured RNAs for destruction. Here, we show for the first time that small molecules targeting structured, disease-causing RNAs can shunt them towards native decay pathways by affecting their processing. SUMMARYMyotonic dystrophy type 2 (DM2) is a genetically defined muscular dystrophy caused by a toxic expanded repeat of r(CCUG) [heretofore (CCUG) exp ], harbored in intron 1 of CHC-Type Zinc Finger Nucleic Acid Binding Protein (CNBP) pre-mRNA. This r(CCUG) exp causes DM2 via a gain-offunction mechanism that results in three hallmarks of its pathology: (i) binding to RNA-binding proteins (RBPs) that aggregate into nuclear foci; (ii) sequestration of muscleblind-like-1 (MBNL1) protein, a regulator of alternative pre-mRNA splicing, leading to splicing defects; and (iii) retention of intron 1 in the CNBP mRNA. Here, we find that CNBP intron retention is caused by the r(CCUG) exp -MBNL1 complex and can be rescued by small molecules. We studied two types of small molecules with different modes of action, ones that simply bind and ones that can be synthesized by a r(CCUG) exp -templated reaction in cells, that is the RNA synthesizes its own drug.Indeed, our studies completed in DM2 patient-derived fibroblasts show that the compounds disrupt the r(CCUG) exp -MBNL1 complex, reduce intron retention, subjecting the liberated intronic r(CCUG) exp to native decay pathways, and rescue other DM2-associated cellular defects.Collectively, this study shows that small molecules can affect RNA biology by shunting toxic transcripts towards native decay pathways. processing will be required to understand and capture the full potential of compounds to target RNA and rescue disease biology. The development of chemical probes and lead medicines targeting structured RNA, particularly human RNAs, are in their infancy. It will be interesting to see the types of chemical structures, their features, and the functional responses that emerge.

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“…Previously, we have shown that for some RNA targets, structure-specific recognition can be advantageous in disease-affected cells and animal models over sequence-specific recognition (33)(34)(35)(36). For example, r(CUG) repeat expansions that cause myotonic dystrophy type 1 form a robustly folded structure that can be targeted selectively with structure-binding small molecules over transcripts with short, unstructured stretches of r(CUG) repeats (37).…”

Section: Discussionmentioning

confidence: 99%

Small molecules exploiting structural differences within microRNA-200 precursors family members reverse a type 2 diabetes phenotype

Haniff

Liu

Knerr

et al. 2020

Preprint

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MicroRNA families are pervasive in the human transcriptome, but specific targeting of individual members is a challenge because of sequence homology. Many of the secondary structures of the precursors to these miRs (pre-miRs), however, are quite different. Here, we demonstrate both in vitro and in cellulis that design of structure-specific small molecules can inhibit specific miR family members to modulate a disease pathway. In particular, the miR-200 family consists five miRs, miR-200a, -200b, -200c, -141, and -429, and is associated with Type II Diabetes (T2D). We designed a small molecule that potently and selectively targets pre-miR-200c's structure. The compound reverses a proapoptotic effect in a pancreatic β-cell model. In contrast, oligonucleotides targeting the RNA's sequence inhibit all family members. Global proteomics analysis further demonstrates selectivity for miR-200c. Collectively, these studies establish that miR-200c plays an important role in T2D and that small molecules targeting RNA structure can be an important complement to oligonucleotides targeting sequence.

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Comparison of small molecules and oligonucleotides that target a toxic, non-coding RNA

Cited by 16 publications

References 23 publications

Insights into the development of chemical probes for RNA

Insights into the development of chemical probes for RNA

A Toxic RNA Catalyzes the Cellular Synthesis of Its Own Inhibitor, Shunting It to Endogenous Decay Pathways

Small molecules exploiting structural differences within microRNA-200 precursors family members reverse a type 2 diabetes phenotype

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